Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of dilated cardiomyopathy in iPSC...

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Molecular Medicine

Background:

• Mutations in the nuclear envelope protein lamin A/C (LMNA) are linked to severe dilated cardiomyopathy (DCM) and early-onset arrhythmias.
• The precise molecular mechanisms driving arrhythmogenesis in LMNA-related DCM (LMNA-DCM) are not fully understood.

Purpose of the Study:

• To investigate the molecular basis of arrhythmias in LMNA-DCM using patient-derived cells.
• To elucidate the role of lamin A/C, calcium handling, and oxidative stress in LMNA-DCM pathogenesis.

Main Methods:

• Utilized induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LMNA-DCM patients.
• Analyzed nuclear envelope structure, calcium handling, protein interactions (lamin A/SIRT1), mitochondrial function, and reactive oxygen species (ROS) production.

Main Results:

• A frameshift LMNA mutation caused abnormal Ca2+ handling, arrhythmias, and nuclear envelope deformation in patient iPSC-CMs.
• Mutant lamin A/C accelerated SIRT1 degradation, inducing mitochondrial dysfunction and oxidative stress.
• Elevated ROS activated the CaMKII-RYR2 pathway and increased SUN1 accumulation, contributing to arrhythmias and nuclear envelope defects.

Conclusions:

• Lamin A/C deficiency-mediated ROS disorder is central to LMNA-DCM development.
• Dysregulation of SIRT1 and oxidative stress are key pathological mechanisms.
• Targeting SIRT1 activity and oxidative stress represents a potential therapeutic strategy for LMNA-DCM.